Proteomic and Genomic Biomarkers for Age-Related Macular Degeneration

Abstract

Toward early detection of susceptibility to age-related macular degeneration (AMD), we quantified plasma carboxyethylpyrrole (CEP) oxidative protein modifications and CEP autoantibodies by ELISA in 916 AMD and 488 control donors. Mean CEP adduct and autoantibody levels were elevated in AMD plasma by ∼60 and ∼30%, respectively, and the odds ratio for both CEP markers elevated was ∼3-fold greater in AMD than in control patients. Genotyping was performed for AMD risk polymorphisms associated with age-related maculopathy susceptibility 2 (ARMS2), high-temperature requirement factor A1 (HTRA1), complement factor H (CFH), and complement C3. The AMD risk predicted for those exhibiting elevated CEP markers and risk genotypes was 2- to 3-fold greater than the risk based on genotype alone. AMD donors carrying the ARMS2 and HTRA1 risk alleles were the most likely to exhibit elevated CEP markers. Receiver operating characteristic curves suggest that CEP markers alone can discriminate between AMD and control plasma donors with ∼76% accuracy and in combination with genomic markers, provide up to ∼80% discrimination accuracy. CEP plasma biomarkers, particularly in combination with genomic markers, offer a potential early warning system for predicting susceptibility to this blinding disease.

Autoimmune Biomarkers in Age-Related Macular Degeneration: A Possible Role Player in Disease Development and Progression

“…These fi ndings have recently been reappraised (Gu et al 2003b(Gu et al , 2009(Gu et al , 2010Patel et al 2005 ;Cherepanoff et al 2006 ) . Studies on murine tissues (Patel et al 2005 ) indicate that, in AMD, auto-Abs develop not only against the neuroretina (nRet), but also RPE and choroid/Bruch's membrane (Ch/BM).…”

“…CEP is pro-angiogenic (Ebrahem et al 2006 ) and CEP-modifi ed adducts develop from oxidation of DHA, which is very abundant in photoreceptor outer segments. Immunization of mice against CEP leads to the development of AMD-like lesions (Hollyfi eld et al 2008 ) , and CEP serum levels and genetic markers together are highly predictive of the likelihood of having exudative AMD (Gu et al 2009(Gu et al , 2010 . We propose that further studies aimed at discovering additional markers can prove useful in understanding other AMD manifestations.…”

“…Highly specifi c and sensitive auto-Abs against carboxy-ethyl-pyrrole (CEP)-modifi ed adducts have been found in AMD sera (Gu et al 2003b(Gu et al , 2009(Gu et al , 2010 . CEP is pro-angiogenic (Ebrahem et al 2006 ) and CEP-modifi ed adducts develop from oxidation of DHA, which is very abundant in photoreceptor outer segments.…”

Seeing through VEGF: innate and adaptive immunity in pathological angiogenesis in the eye

“…CEP has previously been shown in animals to initiate an immune response that leads to damage to the RPE similar to that seen in non-neovascular AMD [85-87]. In addition, not only is CEP increased in AMD donor eyes, but autoantibodies to CEP and CEP-modified proteins can be identified in plasma from AMD patients [88, 89]. The mechanism by which CEP induces an immune response is thought to be via the activation of T lymphocytes by classically activated M1 macrophages [77].…”

Genetics of Age-Related Macular Degeneration: Current Concepts, Future Directions

“…224 Subsequently, it has been shown that CEP adduct and autoantibodies are elevated in the plasma of AMD patients vs. controls and may serve as a biomarker for AMD. 227 …”